Bipolar affective disorder is a severe mental illness which exhibits familial clustering but a complex mode of transmission. Our whole genome search involves the use of a 22-multiplex pedigree series, which so far, yielded two broad susceptibility regions: on the pericentromeric region of chromosome 18 and, on 21q. Recently, regions of increased allele sharing between affected siblings have been found on chromosomes 1q, 5q, 11p14-q13, 11q22-q24, and 22q, which require follow-up studies. The second pedigree series we used for genome scan consists of 97 families, collected by four collaborating centers through the NIMH Genetics Initiative for Bipolar Disorder. Our center has so far completed about 70,000 genotypes with markers on chromosomes 4, 7, 9, 18, 19, 20 and 21q. In this study, we found support for the presence of a susceptibility region on 21q, therefore, increasing the likelihood for a vulnerability gene for bipolar disorder in this chromosome. As a precursor to positional cloning of a susceptibility gene on the centromeric region of chromosome 18, we have saturated the region with new markers, demonstrating the highest allele sharing at 18p11.2. To generate a fine map of 18p11.2, we have ordered and determined the intermarker distances of transcripts, sequence tag sites (STSs), and expressed sequence tags (ESTs) by mapping with a contiguous array of clones in yeast artificial chromosome (YAC), a subchromosomal somatic cell hybrid panel and a radiation hybrid (RH) panel. Included in this area were four of 25 novel, brain-expressed chromosome 18 transcripts that we have isolated. One of these was C18orf1 which we found to have multiple, differentially expressed variants, encoded by at least six exons, and displayed RNA editing in the 5' untranslated region. We also cloned the full-length transcript for a new myo-inositol monophosphatase cDNA, we refer to as IMP.18p, which we RH mapped to 18p11.2. This enzyme is an important candidate gene since it is the presumed target of lithium, a commonly used drug to treat bipolar disorder.